Polysubstituted indan-1-ol systems for the prophylaxis or treatment of obesity

ABSTRACT

Polysubstituted indan-1-ol compounds of formula I, its physiologically acceptable salts and physiologically functional derivatives are disclosed  
                 
 
     Compositions comprising the same, methods of preparation and methods for the prophylaxis or treatment of obesity are also disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The instant application takes priority from DE 10142659.3, filedAug. 31, 2001, which is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to polysubstituted indan-1-ol compounds andtheir physiologically acceptable salts and physiologically functionalderivatives for the prophylaxis or treatment of obesity.

[0004] 2. Description of the Related Art

[0005] WO 97/20806 discloses cyclopentyl-substituted indan-1-olderivatives as antiinflammatory substances.

SUMMARY OF THE INVENTION

[0006] In a preferred embodiment, the invention provides compounds whichcan be used for reducing weight in mammals and which are suitable forpreventing and treating obesity. The instant compounds have atherapeutically utilizable anorectic action.

[0007] In another preferred embodiment, the invention also provides apharmaceutical composition comprising an effective amount of a compoundof formula I. The pharmaceutical composition may also comprise one ormore active compounds suitable for reducing weight or for the treatmentof obesity. The instant composition may also comprise one or morecompounds suitable for treatment of other disorders.

[0008] In another preferred embodiment, the instant invention provides amethod for treating obesity, comprising administering to a subject inneed thereof, an effective amount of a compound according to formula I.

[0009] In another preferred embodiment, the instant invention provides amethod of reducing weight in a mammal, comprising administering to saidmammal an effective amount of a compound of formula I.

[0010] Additional objects, features and advantages of the invention willbe set forth in the description which follows, and in part, will beobvious from the description, or may be learned by practice of theinvention. The objects, features and advantages of the invention may berealized and obtained by means of the instrumentalities and combinationsparticularly pointed out in the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The invention relates to compounds of the formula (I)

[0012] in which

[0013] R1, R2, R3, and R4, independently of one another, are H, F, Cl,Br, I, CN, N3, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CH₂-phenyl, O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,wherein the alkyl radicals, up to seven hydrogen atoms may be replacedby fluorine;

[0014] S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, wherein thealkyl radicals, up to seven hydrogen atoms may be replaced by fluorine;

[0015] NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]2,N[(C₃-C₈)-cycloalkyl]2, NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl;

[0016] SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl;

[0017] SO₂—(C₁-C₆)-alkyl; NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,COO(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂;

[0018] (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, wherein the alkyl, alkenyl and alkynyl groups one toseven hydrogen atoms may be replaced by fluorine;

[0019] or one hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂—Ph,

[0020] NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;

[0021] phenyl, 1- or 2-naphthyl,

[0022] 5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-5-tetrazolyl,2-[(C₁-C₆)-alkyl]-5-tetrazolyl,

[0023] 1-imidazolyl,

[0024] 1- or 4-[1,2,4]-triazolyl,

[0025] 2- or 3-thienyl,

[0026] 2- or 3-furyl,

[0027] 2-, 3- or 4-pyridyl,

[0028] 2-, 4- or 5-oxazolyl,

[0029] 3-, 4- or 5-isoxazolyl,

[0030] 2-, 4- or 5-thiazolyl,

[0031] 3-, 4- or 5-isothiazolyl,

[0032] where the aryl radical or heterocycle may be substituted up totwo times by

[0033] F, Cl, Br, CN,

[0034] OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,NH₂, NH—SO₂—(C₁-C₄)-alkyl;

[0035] COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein the alkyl groups oneto seven hydrogen atoms may be replaced by fluorine; or

[0036] R2 and R3 together form the radical —O—CH₂—O—;

[0037] X is S, SO, SO2;

[0038] Y is (CH2)p, wherein p may be 0, 1, 2 or 3;

[0039] R5 is (C₁-C₁₈)-alkyl, (C₃-C₈)-cycloalkyl,

[0040] wherein the alkyl groups up to seven hydrogen atoms may bereplaced by fluorine;

[0041] (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;CH₂—CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂;

[0042] phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,where the rings or ring systems are in each case substituted up to threetimes by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH2, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl;

[0043] SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl;NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case, one to seven hydrogen atoms may be replacedby fluorine;

[0044] R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆₋CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine;

[0045] R15 is H, C(O)—(C₁-C₆)-alkyl;

[0046] R16 is OH, O (C₁-C₆)-alkyl, NH₂,

[0047] R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₈)-cycloalkyl, wherein thealkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may bereplaced by fluorine;

[0048] R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, wherein the alkyl or cycloalkyl radicals up to sevenhydrogen atoms may be replaced by flourine atoms;

[0049] R9, R12, R14 independently of one another are phenyl, 1- or2-naphthyl, biphenyl, or a heterocyclic radical, where the rings or ringsystems are in each case substituted up to three times by F, Cl, Br, I,CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂;

[0050] (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl groups ineach case one to seven hydrogen atoms may be replaced by fluorine;

[0051] and their physiologically acceptable salts.

[0052] In a preferred embodiment, the invention provides compounds ofthe formula I in which

[0053] R1, R2, R3, R4, independently of one another, are H, F, Cl, Br,N₃, O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups one toseven hydrogen atoms may be replaced by fluorine;

[0054] wherein each case at least one of the radicals R1, R2, R3 and R4is different from hydrogen;

[0055] X is S, SO, SO₂;

[0056] Y is (CH₂)_(p), wherein p may be 0, 1, 2 or 3;

[0057] R5 is (C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl,

[0058] wherein the alkyl groups up to seven hydrogen atoms may bereplaced by fluorine;

[0059] (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;

[0060] CH₂—CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl andR11 may be OH, O—(C₁-C₆)-alkyl or NH₂;

[0061] phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,where the rings or ring systems are in each case substituted up to threetimes by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine;

[0062] R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine;

[0063] R15 is H, C(O)—(C₁-C₆)-alkyl;

[0064] R16 is OH, O—(C₁-C₆)-alkyl, NH₂;

[0065] R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₈)-cycloalkyl, wherein thealkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may bereplaced by fluorine;

[0066] R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, wherein the alkyl or cycloalkyl radicals up to sevenhydrogen atoms may be replaced by fluorine atoms;

[0067] R9, R12, R14 independently of one another are

[0068] phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical,where the rings or ring systems are in each case substituted up to threetimes by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine;

[0069] and their physiologically acceptable salts.

[0070] In another preferred embodiment, the invention provides compoundsof the formula I in which

[0071] R1, R2, R3, R4, independently of one another, are H, F, Cl, Br,N₃, O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups one toseven hydrogen atoms may be replaced by fluorine;

[0072] wherein each case at least one of the radicals R1, R2, R3 and R4is different from hydrogen;

[0073] X is SO₂;

[0074] Y is (CH₂)_(p), wherein p may be 0, 1 or 2;

[0075] R5 is (C₁-C₈)-alkyl, wherein the alkyl group up to seven hydrogenatoms may be replaced by fluorine;

[0076] R6 is F, Cl, Br, CN, (C₁-C₈)-alkyl, wherein the alkyl group up toseven hydrogen atoms may be replaced by fluorine;

[0077] R7 is H, (C₁-C₁₂)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine;

[0078] R8 is (C₁-C₁₂)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine;

[0079] and their physiologically acceptable salts.

[0080] The invention also contemplates compounds of the formula I in theform of their racemates, racemic mixtures and pure enantiomers, and alsoto their diastereomers and mixtures thereof.

[0081] The alkyl, alkenyl and alkynyl radicals in the substituents R1,R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be straight-chainor branched.

[0082] Heterocycle or heterocyclic radical is to be understood asmeaning ring systems which, in addition to carbon, also containheteroatoms, such as, for example, nitrogen, oxygen or sulfur. Thisdefinition furthermore includes ring systems in which the heterocycle orheterocyclic radical is fused with benzene rings.

[0083] Preferred heterocycles or heterocyclic radicals are:

[0084] heteroaryls, such as

[0085] benzimidazolyl,

[0086] 1-[(C₁-C₆)-alkyl]benzimidazolyl,

[0087] imidazolyl,

[0088] 2- or 3-thienyl,

[0089] 2- or 3-furyl,

[0090] benzoxazolyl,

[0091] benzothiazolyl,

[0092] 2-, 3- or 4-pyridyl,

[0093] pyrimidinyl,

[0094] 4-, 5- or 6-pyridazin-2H-yl-3-one,

[0095] 4-, 5- or 6-pyridazin-2-(C₁-C₈)-alkyl-2H-yl-3-one,

[0096] 2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one,

[0097] 3- or 4-pyridazinyl,

[0098] 2-, 3-, 4- or 8-quinolinyl,

[0099] 1-, 3- or 4-isoquinolinyl,

[0100] 1-phthalazinyl,

[0101] 3- or 4-cinnolinyl,

[0102] 2- or 4-quinazolinyl,

[0103] 2-pyrazinyl,

[0104] 2-quinoxalinyl,

[0105] 2-, 4- or 5-oxazolyl,

[0106] 3-, 4- or 5-isoxazolyl,

[0107] 2-, 4- or 5-thiazolyl,

[0108] 3-, 4- or 5-isothiazolyl,

[0109] 1-[(C₁-C₆)-alkyl]-2-, -4- or -5-imidazolyl,

[0110] 3-, 4- or 5-pyrazolyl,

[0111] 1-[(C₁-C₆)-alkyl]-3-, -4- or -5-pyrazolyl,

[0112] 1- or 4-[1,2,4]triazolyl,

[0113] 4- or 5-[1,2,3]triazolyl,

[0114] 1-[(C₁-C₆)-alkyl]-4- or -5-[1,2,3]triazolyl,

[0115] 3-, 4- or 7-indolyl,

[0116] N-[(C₁-C₆)-alkyl]-3-, -4- or -7-indolyl

[0117] 2-[(C₁-C₆)-alkyl]-3(2H)-indazolyl,

[0118] 1-[(C₁-C₆)-alkyl]-3(1H)-indazolyl,

[0119] 5-tetrazolyl,

[0120] 1-[(C₁-C₆)-alkyl]-1H-tetrazolyl,

[0121] 2-[(C₁-C₆)-alkyl]-2H-tetrazolyl.

[0122] Pharmaceutically acceptable salts are particularly suitable formedical applications, due to their greater solubility in water comparedwith the starting or base compounds. Said salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the formula I aresalts of inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid, andsulfuric acid, and also of organic acids such as, for example, aceticacid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonicacid, fumaric acid, gluconic acid, glycolic acid, isethionic acid,lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonicacid, succinic acid, p-toluenesulfonic acid, tartaric acid andtrifluoroacetic acid, furthermore L-ascorbic acid, salicylic acid,1,2-benzisothiazol-3(2H)-one and 6-methyl-1,2,3-oxathiazin-4(3H)-one2,2-dioxide. For medicinal purposes, particular preference is given tousing the chlorine salt. Suitable pharmaceutically acceptable basicsalts are ammonium salts, alkali metal salts (such as sodium salts andpotassium salts), and alkaline earth metal salts (such as magnesiumsalts and calcium salts).

[0123] Salts having a pharmaceutically unacceptable anion are likewiseincluded within the scope of the present invention as usefulintermediates for preparing or purifying pharmaceutically acceptablesalts and/or for use in nontherapeutic applications, for example invitro applications.

[0124] The term “physiologically functional derivative” used hereinrelates to any physiologically acceptable derivative of an inventivecompound, for example, an ester which on administration to a mammal, forexample, humans, is capable of forming (directly or directly) such acompound or an active metabolite thereof.

[0125] A further aspect of this invention is the use of prodrugs of thecompounds of the formula I. Such prodrugs may be metabolized in vivo toa compound of the formula I. These prodrugs may or may not be activethemselves.

[0126] The physiologically functional derivatives furthermore include,for example, glucuronides, sulfuric acid esters, glycosides andribosides.

[0127] The compounds of the formula I may also be present in variouspolymorphous forms, for example, as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theformula I are included within the scope of the invention and are anotheraspect of the invention.

[0128] All references to “compound(s) according to formula (I)” referhereinbelow to a compound/compounds of the formula (I) as describedabove and also to their salts, solvates and physiologically functionalderivatives as described herein.

[0129] A “subject” may be a mammal, and is preferably a human.

[0130] The amount and effective amount of a compound according toformula (I) which is required in order to attain the desired biologicaleffect depends on a number of factors, or example, the specific compoundselected, the intended use, the type of administration and the clinicalstate of the patient. In general, the daily dose is in the range from0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram ofbody weight, or example, 3-10 mg/kg/day. An intravenous dose can be, forexample, in the range from 0.3 mg to 1.0 mg/kg and can be administeredin a suitable manner as an infusion of 10 ng to 100 ng per kilogram perminute. Suitable infusion solutions for these purposes may contain, forexample, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg permilliliter. Individual doses may contain, for example, from 1 mg to 10 gof the active compound. Thus, ampules for injections can contain, forexample, from 1 mg to 100 mg, and orally administerable individual doseformulations such as, for example, tablets or capsules can contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the caseof pharmaceutically acceptable salts, the above mentioned masses relateto the mass of the benzothiazepine ion on which the salt is based. Thecompound used for the prophylaxis or therapy of the above mentionedconditions may be the compounds according to formula (I) themselves, butthey are preferably present in the form of a pharmaceutical compositiontogether with an acceptable carrier. The carrier must be naturallyacceptable, in the sense that it is compatible with the otheringredients of said composition and is not harmful to the patient'shealth. The carrier may be a solid or a liquid, or both, and ispreferably formulated with the compound as an individual dose, forexample, as a tablet which may contain from 0.05% to 95% by weight ofthe active compound. Further pharmaceutically active substances may alsobe present, including further compounds according to formula (I). Thepharmaceutical compositions of the invention may be prepared accordingto any of the known pharmaceutical methods which essentially comprisemixing the ingredients with pharmacologically acceptable carriers and/orexcipients.

[0131] Pharmaceutical compositions of the invention are those which aresuitable for oral, rectal, topical, peroral (e.g. sublingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable manner ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed-release formulations are alsoincluded within the scope of the invention. Preference is given toacid-resistant and enteric formulations. Suitable enteric coatingsinclude cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate, and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0132] Suitable pharmaceutical compounds for oral administration may bepresent in separate units as, for example, capsules, cachets, lozenges,or tablets, which in each case contain a particular amount of thecompound according to formula (I); as powders or granules; as solutionsor suspensions in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. As already mentioned, said compositions may beprepared according to any suitable pharmaceutical method which includesa step in which the active compound and the carrier (which may compriseone or more additional components) are contacted. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely dispersed solid carrier,after which the product is shaped, if necessary. Thus, a tablet, forexample, may be prepared by pressing or shaping a powder or granules ofthe compound, where appropriate, with one or more additional components.Pressed tablets may be prepared by tableting the compound infree-flowing form, for example, a powder or granules, mixed, whereappropriate, with a binder, lubricant, inert diluent and/or one or moresurface active/dispersing agents in a suitable machine. Shaped tabletscan be prepared by shaping the pulverulent compound, moistened with aninert liquid diluent, in a suitable machine.

[0133] Pharmaceutical compositions which are suitable for peroral(sublingual) administration include lozenges which contain a compoundaccording to formula (I) with a flavoring, usually sucrose and gumarabic or tragacanth, and pastilles which comprise the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

[0134] Suitable pharmaceutical compositions for parenteraladministration preferably comprise sterile aqueous preparations of acompound according to formula (I) which are preferably isotonic with theblood of the intended recipient. These preparations are preferablyadministered intravenously, although they may also be administeredsubcutaneously, intramuscularly or intradermally as an injection. Saidpreparations may preferably be prepared by mixing the compound withwater and rendering the obtained solution sterile and isotonic with theblood. Injectable compositions of the invention generally contain from0.1 to 5% by weight of the active compound.

[0135] Suitable pharmaceutical compositions for rectal administrationare preferably present as individual dose suppositories. These may beprepared by mixing a compound according to formula (I) with one or moreconventional solid carriers, for example, cocoa butter, and shaping theresulting mixture.

[0136] Suitable pharmaceutical compositions for topical application tothe skin are preferably present as an ointment, cream, lotion, paste,spray, aerosol or oil. Carriers which may be used are petroleum jelly,lanolin, polyethylene glycols, alcohols, and combinations of two or moreof these substances. In general, the active compound is present at aconcentration of from 0.1 to 15%, for example from 0.5 to 2%, by weightof the composition.

[0137] Transdermal administration is also possible. Suitablepharmaceutical compositions for transdermal administration may bepresent as individual patches which are suitable for long-term closecontact with the epidermis of the patient. Such patches suitably containthe active compound in an optionally buffered aqueous solution,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active compound concentration is from approximately 1 % to 35%,preferably approximately 3% to 15%. A particular possibility is therelease of the active compound by electrotransport or iontophoresis, asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0138] The invention furthermore provides a process for preparing thecompounds of the formula I which comprises obtaining the compounds ofthe formula I by proceeding according to the reaction scheme below:

[0139] To this end, compounds of the formula II,

[0140] in which R1, R2, R3 and R4 are, as defined above, converted witha halogen, such as, for example, bromine or chlorine, into a compound ofthe formula III.

[0141] The compounds of the formula III are converted further with metalsalts of thiols of the formula H—X—Y—R5, wherein X is sulfur and Y andR5 are as defined above into compounds of the formula IV wherein X═S andR6=H. These metal salts can be employed as such or they can be generatedin solution in situ from the thiol and a base, such as, for example,aqueous sodium hydroxide.

[0142] On the other hand, compounds of the formula IV wherein X═S andR6=H can be obtained by reacting compounds of the formula II with abase, such as, for example, lithium diisopropylamide, for example intetrahydrofuran, and with a disulfide of the formula R5-Y—X—X—Y—R5 inwhich R5 and Y are as defined above and X═S; alternatively, instead ofthe disulfide, it is also possible to use a sulfenyl chloride of theformula Cl—X—Y—R5 wherein X═S and Y and R5 are as defined above (see,for example, D. Seebach et al.; Chem. Ber. 109, 1601-1616 (1976)).

[0143] Compounds of the formula IV in which X═S and R6 is not hydrogencan be obtained, for example, as follows: compounds of the formula IIare subjected, for example, to a fluorination, an alkylation or acondensation with an aldehyde and subsequent reduction, giving compoundsof the formula VII which for their part can be converted, for exampleafter bromination, with compounds of the formula M⁺⁻X—Y—R5 wherein X═Sand Y and R5 have the meanings described above into compounds of theformula IV wherein X═S and R6 is not hydrogen.

[0144] Compounds of the formula V in which X═SO and R6 is not hydrogencan be prepared, for example, by selective oxidation of the compound ofthe formula IV in which X═S, using one equivalent ofperoxytrifluoroacetic acid (C. G. Venier et al.; J. Org. Chem. 47, 3773(1982)). The preparation of the sulfoxides from the sulfides can also becarried out using manganese dioxide or chromic acid (D. Edwards et al.;J. Chem. Soc. 1954, 3272). Furthermore suitable for this oxidation ishydrogen peroxide in acetic anhydride (A. V. Sviridova et al.; J. Org.Chem (Russ), English Transl.; 7, 2577(1971)).

[0145] Compounds of the formula VI in which X═SO₂ and R6 is not hydrogencan be obtained by oxidation using, for example, 2KHSO₅×KHSO₄×K₂SO₄(Oxone), either from compounds of the formula IV in which X═S and R6 isnot hydrogen or from compounds of the formula V in which X═SO and R6 isnot hydrogen (see, for example, M. Hudlický, Oxidations in OrganicChemistry, ACS Monograph 186, American Chemical Society, Washington, DC,1990).

[0146] Compounds of the formula VIII in which R8 is not hydrogen, R7 ishydrogen and X═S can be obtained, for example, by reacting compounds ofthe formula IV with a Grignard reagent. Stepwise oxidations andalkylation or acylation reactions give access to compounds of theformulae IX to XIII. Such compounds can also be obtained by employingcompounds of the formula V or VI for the Grignard reaction.

[0147] Inorganic acids suitable for forming salts are, for example:hydrohalic acids, such as hydrochloric acid and hydrobromic acid, andalso sulfuric acid, phosphoric acid and amidosulfonic acid.

[0148] Organic acids suitable for salt formation which may be mentionedare, for example: formic acid, acetic acid, benzoic acid,p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbicacid, salicylic acid, isethionic acid, methanesulfonic acid,trifluoromethanesulfonic acid, 1,2-benzisothiazol-3 (2H)-one,6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

[0149] The examples shown below serve to illustrate the inventionwithout limiting it. The melting points or decomposition points (m.p)measured are uncorrected and generally depend on the heating rate. TABLE1 Examples

Formula I Exam- ple R1 R2 R3 R4 X Y R5 R6 R7 R8 m.p. [° C.] 1 H Cl H HSO₂ — CH₃ F H CH₃ 148 [MH⁺] 2 H Cl H H SO₂ — CH₃ F H CF₃ 333.2

[0150] The compounds of the formula I are distinguished by beneficialactions on the metabolism of lipids, and they are particularly suitablefor weight reduction and, after weight reduction, for maintaining areduced weight in mammals and as anorectic agents. Accordingly, theinstant compounds are, particular useful for treating obesity byreducing weight, maintaining weight loss, and preventing obesity by, forexample, preventing symptoms of weight loss.

[0151] The compounds are distinguished by their low toxicity and theirfew side effects. The compounds may be employed alone or in combinationwith other weight-reducing or anorectic active compounds. Furtheranorectic active compounds of this kind are mentioned, for example, inthe Rote Liste, Chapter 01 (Arzneimittelverzeichnis für Deutschland,published by Rote Liste Service GmbH, Frankfurt) under weight-reducingagents/appetite suppressants, and may also include those activecompounds which increase the energy turnover of the organism and thuslead to weight reduction or else those which influence the generalmetabolism of said organism such that increased calorie intake does notcause an enlargement of the fat depots and a normal calorie intakecauses a reduction in the fat depots of said organism. The compounds aresuitable for the prophylaxis and, in particular, for the treatment ofproblems of excess weight or obesity. The compounds are furthermoresuitable for the prophylaxis and, in particular, for the treatment oftype II diabetes, arteriosclerosis, the normalization of lipidmetabolism, and the treatment of high blood pressure.

[0152] In a further aspect of the invention, the compounds of theformula I may be administered in combination with one or more furtherpharmacologically active substances which may be selected, for example,from the group consisting of antidiabetics, antiadipose agents,blood-pressure-lowering active compounds, lipid reducers, and activecompounds for the treatment and/or prevention of complications caused bydiabetes or associated with diabetes.

[0153] Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2derivatives such as, for example, those disclosed by Novo Nordisk A/S inWO 98/08871 and also oral hypoglycemic active compounds.

[0154] Said oral hypoglycemic active compounds preferably includesulfonyl ureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon receptorantagonists, GLP-1 agonists, potassium channel openers such as, forexample, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO99/03861, insulin sensitizers, activators of insulin receptor kinase,inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, for example glycogenphosphorylase inhibitors, modulators of glucose uptake and glucoseelimination, lipid metabolism-modifying compounds such asantihyperlipidemic active compounds and antilipidemic active compounds,for example HMGCoA-reductase inhibitors, inhibitors of cholesteroltransport/cholesterol uptake, inhibitors of the reabsorption of bileacid or inhibitors of microsomal triglyceride transfer protein (MTP),compounds which reduce food intake, PPAR and RXR agonists and activecompounds which act on the ATP-dependent potassium channel of betacells.

[0155] In one embodiment of the present invention, the present compoundsare administered in combination with insulin.

[0156] In another embodiment, the compounds of the invention areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone,glisoxepide, glibornuride or gliclazide.

[0157] In another embodiment, the compounds of the present invention areadministered in combination with a biguanide such as, for example,metformin.

[0158] In another embodiment, the compounds of the present invention areadministered in combination with a meglitinide such as, for example,repaglinide.

[0159] In yet another embodiment, the compounds of the present inventionare administered in combination with a thiazolidinedione such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0160] In yet another embodiment, the compounds of the present inventionare administered in combination with a monoamine oxidase inhibitor suchas disclosed, for example, in WO 01/12176. Particularly suitable forthis purpose are[3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one,(R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-oneor(R)-5-(methoxymethyl)-3-[6-cyclopropylmethoxybenzofuran-3-yl]oxazolidin-2-one.

[0161] In another embodiment, the compounds of the present invention areadministered in combination with an a-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0162] In yet another embodiment, the present compounds are administeredin combination with an hCNTF (human ciliary neurotrophic factor) orderivatives thereof, such as, for example, CNTF_(AX15) or modifiedCNTF_(AX15), such as disclosed, for example, in Lambert et al., PNAS 98,4652-4657.

[0163] In another embodiment, the compounds of the present invention areadministered in combination with an active compound which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide orrepaglinide.

[0164] In yet another embodiment, the compounds of the present inventionare administered in combination with an antihyperlipidemic activecompound or an antilipidemic active compound such as, for example,cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,probucol, ezetimibe or dextrothyroxine.

[0165] In another embodiment, the compounds of the present invention areadministered in combination with more than one of the aforementionedcompounds, for example in combination with a'sulfonylurea and metformin,a sulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0166] Furthermore, the compounds of the invention may be administeredin combination with one or more antiadipose agents orappetite-controlling active compounds.

[0167] Such active compounds may be selected from the group consistingof CART agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4)agonists, melanin-concentrating hormone (MCH) antagonists, orexinantagonists, H3 agonists, TNF agonists, CRF agonists, CRF BPantagonists, urocortin agonists, β3 adrenoceptor agonists, CCK agonists,serotonin re-uptake inhibitors, mixed serotonin and noradrenalinreuptake inhibitors, 5HT modulators, bombesin agonists, galaninantagonists, glucocorticoid receptor modulators, growth hormone,growth-hormone-releasing compounds, TRH agonists, uncoupling protein 2or 3 modulators, leptin receptor agonists, leptin mimetics, dopamineagonists (bromocriptine, doprexin), lipase/amylase inhibitors,cannabinoid receptor 1 antagonists, modulators of acylation-stimulatingprotein (ASP), PPAR modulators, RXR modulators or TR-β agonists.

[0168] In one embodiment of the invention, the antiadipose agent isleptin or modified leptin.

[0169] In another embodiment, the antiadipose agent is dexamphetamine oramphetamine.

[0170] In another embodiment, the antiadipose agent is fenfluramine ordexfenfluramine.

[0171] In yet another embodiment, the antiadipose agent is sibutramineor the mono- and bis-demethylated active metabolite of sibutramine.

[0172] In another embodiment, the antiadipose agent is orlistate.

[0173] In another embodiment, the antiadipose agent is mazindol,diethylpropione or phentermine.

[0174] Furthermore, the compounds of the present invention may beadministered in combination with one or more antihypertensive activecompounds. Examples of antihypertensive active compounds are betablockers such as alprenolol, atenol, timolol, pindolol, propanolol andmetoprolol, ACE (angiotensin-converting enzyme) inhibitors such as, forexample, benazepril, captopril, enalapril, fosinopril, lisinopril,quinapril and rampril, calcium channel blockers such as nifedipine,felodipine, nicardipine, isradipine, nimodipine, diltiazem andverapamil, and also alpha-blockers such as doxazosin, urapidil, prazosinand terazosin. Furthermore, reference may be made to Remington: TheScience and Practice of Pharmacy, 19th edition, Gennaro, editor, MackPublishing Co., Easton, Pa., 1995.

[0175] It is self-evident that every suitable combination of thecompounds of the invention with one or more of the aforementionedcompounds and optionally one or more other pharmacologically activesubstances is to be regarded as covered by the scope of protection ofthe present invention.

[0176] The following preparations serve to illustrate the invention, butwithout limiting it.

EXAMPLES Example A

[0177] Soft gelatin capsules, comprising 100 mg of active compound percapsule: per capsule Active compound 100 mg Triglyceride mixturefractionated from coconut butter 400 mg Capsule contents 500 mg

Example B

[0178] Emulsion, comprising 60 mg of active compound per 5 ml: per 100ml of emulsion Active compound 1.2 g Neutral oil q.s. Sodiumcarboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s. Glycerol pure0.2 to 2.0 g Flavoring q.s. Water (demineralized or distilled) to 100 ml

Example C

[0179] Rectal drug form, comprising 40 mg of active compound persuppository: per suppository Active compound 40 mg Suppository base ad 2mg

Example D

[0180] Tablets comprising 40 mg of active compound per tablet: pertablet Lactose  600 mg Corn starch  300 mg Soluble starch  20 mgMagnesium stearate  40 mg 1000 mg

Example E

[0181] Coated tablets comprising 50 mg of active compound per coatedtablet: per coated tablet Active compound  50 mg Corn starch 100 mgLactose  60 mg Sec. calcium phosphate  30 mg Soluble starch  5 mgMagnesium stearate  10 mg Colloidal silica  5 mg 260 mg

Example F

[0182] The following recipes are suitable for producing the contents ofhard gelatin capsules: a) Active compound 100 mg Corn starch 300 mg 400mg b) Active compound 140 mg Lactose 180 mg Corn starch 180 mg 500 mg

Example G

[0183] Drops can be prepared according to the following recipe (100 mgof active compound in 1 ml=20 drops: Active compound   10 g Methylbenzoate 0.07 g Ethyl benzoate 0.03 g Ethanol 96%   5 ml Demineralizedwater ad  100 ml

[0184] The activity of the compounds of formula I was assayed asfollows:

[0185] Biological Test Model:

[0186] The anorectic action was tested on female NMRI mice. Afterremoval of feed for 24 hours, the preparation to be tested wasadministered intraperitoneally (i.p.) or by gavage (po). The animalswere housed singly and, with free access to drinking water, they wereoffered evaporated milk 30 minutes after administration of thepreparation. The consumption of evaporated milk was determined and thegeneral behavior of the animals was monitored every half an hour for 7hours. The measured milk consumption was compared to that ofvehicle-treated control animals. TABLE 2 Anorectic action, measured as areduction in the cumulative milk consumption by treated animals comparedwith control animals

Dose [mg/kg] Number of animals/ cumulative milk consumption by treatedanimals N/[ml] Number of animals/ cumulative milk consumption byuntreated control animals N/[ml] Reduction in cumulative milkconsumption as % of the control Example 1 30 (i.p.) 4/2.88 5/3.86 25

[0187] The table indicates that the compounds of the formula I exhibitgood anorectic action.

[0188] The preparation of some examples is described in detail below;the other compounds of the formula I were obtained analogously:

Example 1 5-Chloro-2-fluoro-2-methanesulfonyl-1-methyl-indan-1-ol 1.5-Chloro-2-methylsulfanylindan-1-one

[0189] 0.98 g (4 M-mol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treatedin an ultrasonic bath for 30 minutes and then stirred at roomtemperature for 90 minutes. The reaction mixture is concentrated underreduced pressure and chromatographed on silica gel using toluene/ethylacetate 10/1. The eluates are concentrated under reduced pressure,giving 0.63 g of 5-chloro-2-methylsulfanylindan-1-one of melting point90° C.

2. 5-Chloro-2-methanesulfonylindan-1-one

[0190] 0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1-one isdissolved in 10 ml of methanol; at 0° C., a solution of 4.33 g (7.05mmol) of 2KHSO₅×KHSO₄×K₂SO₄ in 10 ml of water is added dropwise. Themixture is stirred at room temperature for 5 h; the methanol isdistilled off and the aqueous residue is extracted with dichloromethane.The organic phase is separated off, dried over MgSO₄, filtered andconcentrated under reduced pressure. This gives 0.5 g of5-chloro-2-methanesulfonylindan-1-one of melting point 197° C.

3. 5-Chloro-2-fluoro-2-methanesulfonylindan-1-one

[0191] 0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and1.77 g (5 mmol) of N-fluoro-N′-(chloromethyl)triethylenediaminebis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and7.5 ml of acetonitrile and stirred under reflux for 4 h. The reactionmixture is cooled, concentrated under reduced pressure and purifiedchromatographically on silica gel using the mobile phasedichloromethane. This gives5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150° C.

4. 5-Chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol

[0192] At room temperature, 260 mg (1 mmol) of5-chloro-2-fluoro-2-methanesulfonylindan-1-one are dissolved in 10 ml ofdry tetrahydrofuran, and 0.33 ml of a 3M solution of methylmagnesiumbromide in diethyl ether is added dropwise with stirring. The reactionmixture is stirred at 50° C. for 3 h. A further 0.33 ml of themethylmagnesium bromide solution is then added, and the mixture isstirred at room temperature for another hour. After the reaction hasended, the reaction mixture is diluted with ethyl acetate and extractedsuccessively with sat. ammonium chloride solution, sat. sodium bisulfitesolution, sat. sodium bicarbonate solution and sat. sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand concentrated under reduced pressure. Chromatographic purification onsilica gel (n-heptane/ethyl acetate 60/40) gives5-chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol of melting point148° C.

Example 25-Chloro-2-fluoro-2-methanesulfonyl-1-trifluoromethylindan-1-ol

[0193] When 5-chloro-2-fluoro-2-methanesulfonylindan-1-one is, insteadof methylmagnesium bromide, reacted with trifluoromethyltrimethylsilaneand tetrabutylammonium fluoride in tetrahydrofuran,5-chloro-2-fluoro-2-methanesulfonyl-1-trifluoromethylindan-1-ol ofmolecular weight 332.7 (C₁₁H₉ClF₄SO₃); MS (ESI): 333.20 (MH⁺) isobtained.

[0194] Additional advantages, features, and modifications will bereadily apparent to those skilled in the art. Therefore, the inventionin its broader aspects is not limited to the specific details shown anddescribed herein. Accordingly, various modifications may be made withoutdeparting from the spirit or scope of the general inventive concept asdefined bye the appended claims and their equivalents.

[0195] As used herein and in the following claims, articles such as“the”, “a” and “an” can connote the singular or plural.

[0196] All documents referred to herein are specifically incorporatedherein by reference in their entireties.

[0197] The instant priority document, DE 10142659.3 filed Aug. 31, 2001is incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of the formula I,

in which R1, R2, R3, R4 independently of one another are H; F, Cl, Br,I, CN, N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, wherein the alkylradicals up to seven hydrogen atoms may be replaced by fluorine;S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, wherein the alkylradicals up to seven hydrogen atoms may be replaced by fluorine; NH₂,NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂,N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl, orNH—CO—(C₃-C₈)-cycloalkyl; SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; SO₂—(C₁-C₆)-alkyl NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, COO(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl,or (C₂-C₈)-alkynyl, wherein the alkyl, alkenyl and alkynyl groups one toseven hydrogen atoms may be replaced by fluorine; or one hydrogen may bereplaced by OH, OC(O)CH₃, O—CH₂—Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;phenyl, 1- or 2-naphthyl, 5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-5-tetrazolyl,2-[(C₁-C₆)-alkyl]-5-tetrazolyl, 1-imidazolyl, 1- or 4-[1,2,4]-triazolyl,2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, or 3-, 4- or5-isothiazolyl, where the aryl radical or heterocycle may be substitutedup to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃,O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH,CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein the alkyl groups one to sevenhydrogen atoms may be replaced by fluorine; or R2 and R3 together formthe radical —O—CH₂—O—; X is S, SO, or SO₂; Y is (CH₂)_(p), wherein p maybe 0, 1, 2 or 3; R5 is (C₁-C₁₈)-alkyl, or (C₃- C₈)-cycloalkyl, whereinthe alkyl groups up to seven hydrogen atoms may be replaced by fluorine;(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;CH₂—CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂; phenyl, 1- or 2-naphthyl, biphenyl ora heterocyclic radical, where the rings or ring systems are in eachcase-substituted up to three times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine; R15 is H, or C(O)—(C₁-C₆)-alkyl; R16 is OH, O—(C₁-C₆)-alkyl,or NH₂, R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, or COO(C₃-C₈)-cycloalkyl, whereinthe alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms maybe replaced by fluorine; R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine atoms; R9, R12, R14 independently of one another are phenyl, 1-or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings orring systems are in each case substituted up to three times by F, Cl,Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-,cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; and their physiologically acceptable salts.
 2. The compoundsof the formula I, as claimed in claim 1, wherein R1, R2, R3, R4independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or(C₁-C₈)-alkyl and wherein the alkyl groups one to seven hydrogen atomsmay be replaced by fluorine; wherein each case at least one of theradicals R1, R2, R3 and R4 is different from hydrogen; X is S, SO, orSO₂; Y is (CH₂)_(p), wherein p may be 0, 1, 2 or 3; R5 is(C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein thealkyl groups up to seven hydrogen atoms may be replaced by fluorine;(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;CH₂-CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂; phenyl, 1- or 2-naphthyl, biphenyl ora heterocyclic radical, where the rings or ring systems are in each casesubstituted up to three times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl,O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine; R15 is H, or C(O)—(C₁-C₆)-alkyl; R16 is OH, O—(C₁-C₆)-alkyl,or NH₂; R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, or COO(C₃-C₈)-cycloalkyl, whereinthe alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms maybe replaced by fluorine; R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl orcycloalkyl radicals up to seven hydrogen atoms mnay be replaced byfluorine atoms; R9, R12, R14 independently of one another are phenyl, 1-or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings orring systems are in each case substituted up to three times by F, Cl,Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; and their physiologically acceptable salts.
 3. The compoundsof the formula I, as claimed in claim 1, wherein R1, R2, R3, R4independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or(C₁-C₈)-alkyl and wherein the alkyl groups one to seven hydrogen atomsmay be replaced by fluorine; wherein each case at least one of theradicals R1, R2, R3 and R4 is different from hydrogen; X is SO₂; Y is(CH₂)_(p), wherein p may be 0, 1 or 2; R5 is (C₁-C₈)-alkyl, wherein thealkyl group up to seven hydrogen atoms may be replaced by fluorine; R6is F, Cl, Br, CN, or (C₁-C₈)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine; R7 is H, or (C₁-C₁₂)-alkyl,wherein the alkyl group up to seven hydrogen atoms may be replaced byfluorine; R8 is (C₁-C₁₂)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine; and their physiologicallyacceptable salts.
 4. A pharmaceutical composition comprising aneffective amount of a compound of formula I as claimed in claim 1, and apharmaceutically acceptable carrier.
 5. The pharmaceutical compositionaccording to claim 4, further comprising one or more active compoundssuitable for reducing weight or for the treatment of obesity.
 6. Thepharmaceutical composition according to claim 4, further comprising oneor more of the agents selected from the group consisting of cathine,phenylpropanolamine, amfepramone, mefenorex, ephedrine, leptin,dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine,orlistat, mazindol or phentermine or their salts for preparing amedicament for reducing weight in mammals.
 7. A method for the treatingobesity, comprising administering to a subject in need thereof, aneffective amount of a compound according to formula I as claimed inclaim
 1. 8. A method of reducing weight in a mammal, comprisingadministering to said mammal an effective amount of a compound offormula I as claimed in claim
 1. 9. A method of maintaining weight loss,comprising administering to a subject in need thereof, an effectiveamount of a compound of formula I as claimed in claim
 1. 10. The methodof claim 9, further comprising administering one or more activecompounds for reducing weight in mammals.